UCLA researchers have discovered a type of cell that is the "missing link" between bone marrow stem cells and all the cells of the human immune system, a finding that will lead to a greater understanding of how a healthy immune system is produced and how disease can lead to poor immune function.

The studies were done using human bone marrow, which contains all the stem cells that produce blood during postnatal life.

"We felt it was especially important to do these studies using human bone marrow as most research into the development of the immune system has used mouse bone marrow," said study senior author Dr. Gay Crooks, co-director of the Eli and Edythe Broad Center of Regenerative Medicine and a co-director of the Cancer and Stem Cell Biology program at UCLA's Jonsson Comprehensive Cancer Center. "The few studies with human tissue have mostly used umbilical cord blood, which does not reflect the immune system of postnatal life."

The research team was "intrigued to find this particular bone marrow cell because it opens up a lot of new possibilities in terms of understanding how human immunity is produced from stem cells throughout life," said Crooks, a professor of pathology and pediatrics.

Understanding the process of normal blood formation in human adults is a crucial step in shedding light on what goes wrong during the process that results in leukemias, or cancers of the blood.

The study appears Sept. 2 in the early online edition of Nature Immunology.

Before this study, researchers had a fairly good idea of how to find and study the blood stem cells of the bone marrow. The stem cells live forever, reproduce themselves and give rise to all the cells of the blood. In the process, the stem cells divide and produce intermediate stages of development called progenitors, which make various blood lineages like red blood cells or platelets. Crooks was most interested in the creation of the progenitors that form the entire immune system, which consists of many different cells called lymphocytes, each with a specialized function to fight infection.

"Like the stem cells, the progenitor cells are also very rare, so before we can study them we needed to find the needle in the haystack." said Lisa Kohn, a member of the UCLA Medical Scientist Training Program and first author in the paper.

Previous work had found a fairly mature type of lymphocyte progenitor with a limited ability to differentiate, but the new work describes a more primitive type of progenitor primed to produce the entire immune system, Kohn said

Once the lymphoid primed progenitor had been identified, Crooks and her team studied how gene expression changed during the earliest stages of its production from stem cells.

"The gene expression data convinced us that we had found a unique stage of development in the immune system. There was a set of genes that the lymphoid-primed cell shares with the bone marrow stem cells and a unique gene expression of its own once it becomes active. This data provided us with an understanding of what genes are important in creating all the cells of the immune system," Crooks said. "The information could allow us to manipulate bone marrow to help create a stronger immune system."

As a bone marrow transplant clinician who treats children with many diseases including leukemia and immune deficiency, Crooks is keenly interested in how the immune system is made and, more specifically, any novel ways there may be to speed that process along in her patients, whose immune system are wiped out prior to the transplant.

"The identification of a progenitor in human bone marrow primed for full lymphoid differentiation will now permit delineation of the molecular regulation of the first stages of lymphoid commitment in human hematopoiesis," the study states. "It will also allow understanding of how these processes are affected during aberrant hematopoiesis in disease states."

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The study was funded by the California Institute of Regenerative Medicine, the National Institutes of Health (PO1 HL073140 and RO1 HL077912), the Broad Stem Cell Research Center at UCLA and UCLA's Jonsson Comprehensive Cancer Center.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2012, the Jonsson Cancer Center was once again named among the nation's top 10 cancer centers by U.S. News & World Report, a ranking it has held for 12 of the last 13 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.

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